Several attempts have been made in the prior art to prepare specific metabolic inhibitors having specific chemotherapeutic applications. The use of 4-bromo-3-hydroxy-hippuric acid and cationic salts thereof has been described by Ellenbogen et al. in U.S. Pat. No. 3,646,121 as useful for inhibiting the formation of histamine in mammals by inhibiting histidine decarboxylase. Likewise, brocresin (4-bromo-3-hydroxybenzyloxamine phosphate) is a known inhibitor of histidine decarboxylase.
Allopurinol or 4-hydroxypyrazole-(3,4-d)-pyrimidine has been described in U.S. Pat. No. 3,474,098 as a useful therapeutic agent for inhibiting the production of uric acid in the purine catabolic cycle by interfering with the activity of xanthine oxidase, but several undesirable side effects have been reported and according to the Physician's Desk Reference 1973, pp. 651-652, the drug is suitable for only limited applications.
The present inventors discovered and disclosed in Japanese Patent Application No. 96778/71 that lecanoric acid, abundantly produced by the fungus of genus Pyricularia, possesses a strong inhibitory activity to an enzyme, histidine decarboxylase, which catalyses the conversion of histidine to histamine. Lecanoric acid, in the previous specification is named as 4-0-(2,4-dihydroxy-6-methyl-benzoyl)-2-hydroxy-6-methyl-benzoic acid, but in this specification, we shall name it as 4'-carboxy-2,3'-dimethyl-4,6,5'-trihydroxyphenylbenzoate, however, was found by the inventors to be hydrolysed in animals thus exhibiting only weak anti-inflammatory activity. The inventors chemically synthesized the compounds of the present invention to seek compounds more stable in animals and having in said activities.
One of the compounds to meet the above requirements is N-(2,4-dihydroxybenzoyl)-4-aminosalicylic acid (which can also be named 4-carboxy-2',3,4'-trihydroxybenzanilide) and its salts, on which a patent application was filed by these inventors as U.S. patent application Ser. No. 349,759 filed Apr. 10, 1973.